The role of the cerebral circulatory system and central nervous system in the pathogenesis of gram-negative endotoxin shock is uncertain. Although several studies have attempted to answer this question, it remains unanswered to date. The current project is designed to explore the involvement of the central nervous system in the pathogenesis of endotoxin shock, with particular emphasis being placed upon the cerebral blood flow, cerebral ischemia and the functional integrity of the vasomotor and cardiac regulatory centers of the medulla. Our work to date has demonstrated that cerebral blood flow is severely depressed during shock and that vascular responsiveness to certain vasoactive substances is altered in a deliterious fashion. Work is currently under progress to evaluate the relationship of the depressed cerebral blood flow and subsequent cerebral ischemia to the pathogenesis of endotoxin shock. Cerebral vascular responsiveness to several naturally occurring vasoactive agents and therapeutic regimens is also being investigated.